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Pulmonary Function Changes in Older Adults with and Without Metabolic www.nature.com/scientificreports OPEN Pulmonary function changes in older adults with and without metabolic syndrome Maysa Alves Rodrigues Brandao‑Rangel1,2*, Renilson Moraes‑Ferreira1,2, Manoel Carneiro Oliveira‑Junior2, Alana Santos‑Dias2, André Luis Lacerda Bachi2,3, Giovana Gabriela‑Pereira2, Simone de Oliveira Freitas2, Amanda Cristina Araújo‑Rosa1,2, Luis Vicente Franco Oliveira4, Claudio Ricardo Frison2, Wagner Luiz do Prado5, Raghavan Pillai Raju6, P Babu Balagopal7,8,9 & Rodolfo P Vieira1,2,10 The low‑grade infammation associated with metabolic syndrome (MS) triggers functional and structural alterations in several organs. Whereas lung function impairment is well reported for older adult population, the efect of MS on functional and immunological responses in the lungs remains unclear. In this cross‑sectional study we determined whether MS alters pulmonary function, and immunological responses in older adults with MS. The study sample consisted of older adults with MS (68 ± 3 years old; n = 77) and without MS (67 ± 3 years old; n = 77). Impulse oscillometry was used to evaluate airway and tissue resistance, and reactance. Biomarkers of infammation and fbrosis were assessed in the blood and in breath condensate. The total resistance of the respiratory system (R5Hz; p < 0.009), and the resistance of the proximal (R20Hz; p < 0.001) and distal (R5Hz–R20Hz; p < 0.004) airways were higher in MS individuals compared to those without MS. Pro‑infammatory (leptin, IL‑1beta, IL‑8, p < 0.001; TNF‑alpha, p < 0.04) and anti‑infammatory cytokines (adiponectin, IL‑1ra, IL‑10, p < 0.001), anti‑fbrotic (relaxin 1, relaxin 3, Klotho, p < 0.001) and pro‑fbrotic (VEGF, p < 0.001) factors were increased in sera and in breath condensate individuals with MS. The results show that MS adversely afect lung mechanics, function, and immunological response in older adults. The data ofer a metabolic basis for the infammaging of the lungs and suggest the lungs as a potential therapeutic target for controlling the immune response and delaying the onset of impaired lung function in older adults with MS. Metabolic syndrome (MS) is characterized by the coexistence of at least three of the following clinical features: abdominal obesity (AO), hyperglycemia, hypertriglyceridemia, hypertension and low levels of high-density lipoprotein (HDL)1. MS is also associated with low-grade infammation characterized by increased circulating levels of pro-infammatory factors, such as interleukin (IL) -1beta, IL-8, tumor necrosis factor alpha (TNF- alpha), leptin, resistin as well as pro-fbrotic growth factors, such as vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-beta)2. A heightened and chronic state of infammation in older adults, frequently referred to as infammaging, accelerates the biological aging process and exposes individuals to altered immune responses leading to immunosenescence. In individuals with MS compared to those without 1Post-Graduation Program in Sciences of Human Movement and Rehabilitation, Federal University of Sao Paulo (UNIFESP), Avenida Ana Costa 95, Santos, SP 11060-001, Brazil. 2Brazilian Institute of Teaching and Research in Pulmonary and Exercise Immunology (IBEPIPE), Rua Pedro Ernesto 240, São José dos Campos, SP 12245-520, Brazil. 3Department of Otorhinolaryngology, Federal University of São Paulo (UNIFESP), Rua Pedro de Toledo 947, São Paulo 04039-032, Brazil. 4Post-Graduation Program in Human Movement and Rehabilitation, UniEvangélica, Avenida Universitária Km 3,5, Anápolis, GO 75083-515, Brazil. 5Kinesiology Department, California State University San Bernardino, San Bernardino, CA, USA. 6Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, USA. 7Nemours Children’s Health Systems, Jacksonville, FL, USA. 8Mayo Clinic College of Medicine, Jacksonville, FL, USA. 9Mayo Clinic College of Medicine, Rochester, MN, USA. 10Post-Graduation Program in Bioengineering, Universidade Brasil, Rua Carolina Fonseca 235, São Paulo, SP 08230-030, Brazil. *email: [email protected] Scientifc Reports | (2021) 11:17337 | https://doi.org/10.1038/s41598-021-96766-x 1 Vol.:(0123456789) www.nature.com/scientificreports/ MS, infammaging and immunosenescence are more pronounced and may induce structural and functional alterations in multiple organ systems, accelerating the overt manifestation of various diseases such as cardio- vascular disease (CVD) and type II diabetes mellitus (T2DM)3,4. Additionally, the aging process itself entails obligatory changes in various body systems leading to drastic derangements including that in the respiratory system5. However, there is a paucity of information on the intrinsic changes in infammatory status within the respiratory system of older adults with MS. Although some controversy exists as to whether MS is a unique disease entity, its individual components have independently been associated with changes in pulmonary function and or lung diseases in humans6. Te infuence of MS on lung mechanics (indicating structural alterations) and pulmonary immune response, however, remains less clear, particularly in older adults. In fact, chronic respiratory diseases appear to be more frequent in individuals with morbid obesity and MS vs those without MS7. Previous studies have also reported correla- tions between systemic infammation and reduced pulmonary function8. A recent pre-clinical study showed that obesity induced the development of a specifc pro-infammatory and pro-fbrotic lung phenotype, which might alter lung function 9, suggesting the potential obesity-related alterations in lung function. In the present study, we tested the hypothesis that in older adults with MS, the pro-infammatory and pro-fbrotic responses in the respiratory system may enhance the loss of pulmonary function and impaired lung mechanics. Methods Patient selection. Older adult women and men for the study were recruited in the Center for Social, Sports and Health Care for Older adults from the municipality of the city of São José dos Campos – SP, Brazil. World Health Organization (WHO) criteria for older adults defned as 60 years of age or older 10 was used for recruitment. For inclusion in the study the participants should be able to perform spirometry evaluation (forced maneuver). Exclusion criteria included, (i) history of smoking, (ii) diagnosis of respiratory disease, (iii) chronic degenerative, autoimmune or neurological diseases, (iv) regular physical activity. From a total 807 potential participants screened for the study, 77 (68 ± 3 years old; 26 men, 51 women) with MS and 77 (67 ± 3 years old; 21 men, 56 women) without MS were randomly selected for this study. Te diagnosis of MS was performed according to the American Heart Association’s diagnostic criteria1. Briefy, individuals presenting at least three of the following characteristics were classifed as with MS: abdominal obe- sity (waist circumference t ≥ 102 cm for men and ≥ 88 cm for women); hyperglycemia (hyperinsulinemia: top 25% of fasting insulin values from non-diabetic population), hypertriglyceridemia (triglycerides ≥ 1.7 mmol/L), hypertension (blood pressure > 130/85 mm Hg) and low levels of high-density lipoprotein (Low HDL choles- terol: < 1.03 mmol/L (male), < 1.3 mmol/L (female)1. Informed consent was obtained from all subjects afer the nature of the study had been explained. Te pre- sent study and all procedures performed were approved by the ethical committee of University of Sao Paulo (53344616.6.0000.5511) and appropriate consents were obtained from the participants included in the study according to the national recommendations for clinical studies, in agreement with Declaration of Helsinki. Clinical, biochemical and anthropometric evaluation. All volunteers were systematically evaluated and followed by a geriatrician from older adults of the municipality of São José dos Campos. Te age (years), body mass (Kg), height (m), body mass index (BMI), and waist circumference (cm), were measured as part of the clinical evaluation of the volunteers. Te venous blood (5 mL) was collected from each subject using vacuum tubes and 25 µl of the total blood was immediately used for the whole blood hematology analysis. Te remaining blood was centrifuged at 900 g, 4 °C, for 7 min and the serum was stored at – 86 °C until analysis. Biochemical measurements consisted of total cholesterol (Code-REF76), HDL cholesterol (Code-REF13) and triglycerides (Code-REF87) in the sera by using commercial colorimetric kits from Labtest (Lagoa Santa, MG, Brazil). Te whole blood analysis (white and red cells) was performed using the automated hematology analyzer (Roche, Sysmex XS-800i, Europe GmbH, Germany). Table 1 summarizes the clinical, biochemical, and anthropometric characteristics of the volunteers. Te serum was used for the quantifcation of infammatory and fbrotic media- tors by enzyme-linked immunosorbent assay (ELISA), by using SpectraMax i3 (Molecular Devices, USA). Breath condensate collection and analysis. Te exhaled breath condensate (BC) was collected using the RT-Tube (Respiratory Research, USA) according to the manufacturer’s instructions. In brief, approximately 1–2 ml of BC was collected from each volunteer in 10–15 min and the samples were stored at – 86 °C until analy- sis. Te BC was used for the quantifcation of infammatory and fbrotic mediators by enzyme-linked immuno- sorbent assay (ELISA), using SpectraMax i3 (Molecular Devices, USA). Measurement of infammatory and fbrotic mediators in serum
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